Nintedanib (BIBF 1120)

Background

Nintedanib (BIBF 1120) is an orally available triple tyrosine kinase inhibitor that can inhibit vascular endothelial growth factor receptor (VEGFR) -1, -2, and -3, fibroblast growth factor receptor (FGFR) -1, -2, and -3, as well as platelet-derived growth factor receptor (PDGFR) α and β tyrosine kinases with an IC₅₀ value of 4.16±0.04μM, 5.62±2.64μM, and 6.32±1.18μM for HNE-1, CNE-2, and HONE-1, respectively^[1-3]. Nintedanib is also a potent antagonist of growth factors such as platelet-derived growth factor, vascular endothelial growth factor, and basic fibroblast growth factor^[2]. Nintedanib has potent antitumor and antiangiogenic activity^[4].

In vitro, after treating Hepatocellular carcinoma (HCC) cells with Nintedanib at different doses (0, 1, 5, 10, 15, 20μM) for 48 hours, Nintedanib significantly induced the accumulation of sub-G1-positive cells and apoptosis, and also significantly induced DNA fragmentation in a dose-dependent manner^[5]. Three human nasopharyngeal carcinoma (NPC) cell lines, CNE-2, HNE-1, and HONE-1, were treated with Nintedanib (0-10μM) for 72 hours, which significantly inhibited the growth of these three cell lines in a dose-dependent manner. The IC₅₀ values for the effect of Nintedanib on HNE-1, CNE-2, and HONE-1 were 4.16±0.04μM, 5.62±2.64μM, and 6.32±1.18μM, respectively^[3].

In vivo, C57BL/6 male mice with lung fibrosis induced by intratracheal bleomycin or silica particles were treated with Nintedanib (30, 60, or 100mg/kg; gavage) daily, which inhibited platelet-derived growth factor (PDGF) receptor activation, fibroblast proliferation and transformation, and significantly reduced bronchoalveolar lavage (BAL) lymphocytes and neutrophils as well as decreased interleukin-1β, keratinocyte chemoattractant (KC), tissue inhibitor of metalloproteinase-1 (TIMP-1) and lung collagen^[6]. After treating nude mice (with human tumor xenografts growing in vivo) with Nintedanib (25-100mg/kg daily p.o.), Nintedanib exerts its effects after 3 days of treatment, reduces vessel density and vessel integrity after 5 days, and induces significant tumor growth inhibition^[7].

参考文献:
[1] Antoniu SA. Nintedanib (BIBF 1120) for IPF: a tomorrow therapy?. Multidiscip Respir Med. 2012;7(1):41.
[2] Santos ES, Gomez JE, Raez LE. Targeting angiogenesis from multiple pathways simultaneously: BIBF 1120, an investigational novel triple angiokinase inhibitor. Invest New Drugs. 2012;30(3):1261-1269.
[3] Xue C, Tian Y, Zhang J, et al. Efficacy of BIBF 1120 or BIBF 1120 plus chemotherapy on nasopharyngeal carcinoma in vitro and in vivo. Drug Des Devel Ther. 2016;10:1173-1180.
[4] Kutluk Cenik B, Ostapoff KT, Gerber DE, Brekken RA. BIBF 1120 (nintedanib), a triple angiokinase inhibitor, induces hypoxia but not EMT and blocks progression of preclinical models of lung and pancreatic cancer. Mol Cancer Ther. 2013;12(6):992-1001.
[5] Tai WT, Shiau CW, Li YS, et al. Nintedanib (BIBF-1120) inhibits hepatocellular carcinoma growth independent of angiokinase activity. J Hepatol. 2014;61(1):89-97.
[6] Wollin L, Maillet I, Quesniaux V, Holweg A, Ryffel B. Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis. J Pharmacol Exp Ther. 2014;349(2):209-220.
[7] Hilberg F, Roth GJ, Krssak M, et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008;68(12):4774-4782.

Nintedanib (BIBF 1120)是一种可口服的三重酪氨酸激酶抑制剂，能够抑制血管内皮生长因子受体（VEGFR）-1、-2和-3，成纤维细胞生长因子受体（FGFR）-1、-2和-3以及血小板衍生生长因子受体（PDGFR）α和β酪氨酸激酶，对HNE-1、CNE-2和HONE-1的半数抑制浓度（IC₅₀）值分别为4.16±0.04μM、5.62±2.64μM和6.32±1.18μM^[1-3]。Nintedanib也是血小板衍生生长因子、血管内皮生长因子和碱性成纤维细胞生长因子等生长因子的强效拮抗剂^[2]。Nintedanib具有强大的抗肿瘤和抗血管生成活性^[4]。

在体外，用不同剂量（0、1、5、10、15、20μM）的Nintedanib处理肝细胞癌（HCC）细胞48小时后，Nintedanib显著诱导了亚G1期阳性细胞的积累和细胞凋亡，并且以剂量依赖性方式显著诱导了DNA片段化^[5]。三种人类鼻咽癌（NPC）细胞系CNE-2、HNE-1和HONE-1用Nintedanib（0-10μM）处理72小时，显著抑制了这三种细胞系的生长，且呈剂量依赖性。Nintedanib对HNE-1、CNE-2和HONE-1的影响的半数抑制浓度（IC₅₀）值分别为4.16±0.04μM、5.62±2.64μM和6.32±1.18μM^[3]。

在体内，对经气管内注射博莱霉素或硅尘颗粒诱导肺纤维化的C57BL/6雄性小鼠，每天进行Nintedanib（30、60、100mg/kg，灌胃）处理，抑制了血小板衍生生长因子（PDGF）受体激活、成纤维细胞增殖和转化，并显著减少了支气管肺泡灌洗液（BAL）中的淋巴细胞和中性粒细胞，降低了白介素-1β、角质形成细胞趋化因子（KC）、金属蛋白酶组织抑制因子-1（TIMP-1）和肺胶原蛋白^[6]。在裸鼠（体内生长人类肿瘤异种移植瘤）中，用Nintedanib（每天口服25-100mg/kg）处理后，Nintedanib在治疗3天后发挥作用，5天后降低血管密度和血管完整性，并诱导显著的肿瘤生长抑制^[7]。

Protocol